Anticonvulsant
PREGNANCY RECOMMENDATION: Human Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Ethosuximide is a succinimide anticonvulsant indicated for the treatment of petit mal epilepsy (1). Ethosuximide has a much lower teratogenic potential than the oxazolidinedione class of anticonvulsants (see also Trimethadione and Paramethadione) (2, 3). However, combination therapy with other anticonvulsants markedly increases the risk of structural anomalies. The succinimide anticonvulsants have been considered the anticonvulsants of choice for the treatment of petit mal epilepsy during the 1st trimester.
FETAL RISK SUMMARY
Ethosuximide has been associated with structural anomalies, but the data are not adequate to prove a definite causal relationship (1). In many of the cases described below, the mother was receiving combination therapy with anticonvulsants known to be human teratogens.
Consistent with its low molecular weight (about 141), the drug crosses the human placenta with many newborns having concentrations within the therapeutic range (1, 4, 5). In eight pregnancies, the mean maternal and fetal ethosuximide concentrations at birth were 40.15 and 35.82 mcg/mL, respectively, with the time of the last dose ranging from 4.5 to 16 hours before birth. The mean fetal:maternal ratio was 0.97 and the neonatal half-life in three infants was 32–38 hours (4). In another case, the plasma drug concentrations in the mother and cord blood were 240 and 250 μmol/L, respectively, a ratio of 1.0 (5).
In 163 pregnancies exposed to ethosuximide in combination with other anticonvulsants, abnormalities were observed in 10 pregnancies: patent ductus arteriosus (8 cases); cleft lip and/or palate (7 cases); mongoloid facies, short neck, altered palmar crease, and an accessory nipple (1 case); and hydrocephalus (1 case) (2,6–15). Spontaneous hemorrhage in the neonate following in utero exposure to ethosuximide also has been reported (see also Phenytoin and Phenobarbital) (12).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 18 newborns had been exposed to ethosuximide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (one expected).
A 1984 publication described the outcomes of 13 newborns from 10 epileptic mothers compared with pair-matched controls (4). Eleven of the mothers received combination therapy with one or more anticonvulsants (carbamazepine, clonazepam, phenobarbital, phenytoin, primidone, or valproic acid). Two infants had major structural anomalies (hare lip and bilateral clefting) with combination therapy (ethosuximide with phenobarbital or primidone). The mean number of minor anomalies was higher compared with controls (6.2 vs. 2.1), but the number and types did not differ from previous reports of anticonvulsant therapy. Sedation and poor sucking were observed in seven infants, six of whom had been exposed in utero to phenobarbital or primidone. Withdrawal symptoms, characterized by hyperexcitability and other symptoms, lasting for several weeks were observed in five infants, two of whom were exposed to phenobarbital or primidone (4).
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was first published in January 1997 (16). The final report was published in July 2010. The Registry is now closed. Among nine prospectively enrolled pregnancies exposed to ethosuximide and lamotrigine, with or without other anticonvulsants, eight were exposed in the 1st trimester resulting in seven live births without defects and one spontaneous abortion. There was one exposure in the 2nd/3rd trimesters resulting in a live birth without defects (16).
A 1992 report analyzed pooled data from five prospective European studies involving 1379 children exposed in utero to anticonvulsants (17). There were 13 pregnancies exposed to ethosuximide monotherapy with 1 major defect, and 44 exposed to combination therapy (5 with phenobarbital and 39 with valproic acid) with 5 major defects. These outcomes were not significantly different in comparison with other anticonvulsants (17).
BREASTFEEDING SUMMARY
Ethosuximide freely enters the breast milk in concentrations similar to the maternal serum. Five reports measured milk:plasma ratios of 0.86–1.0 (4,5,18–20). In one case, the infant’s plasma concentration of ethosuximide was 120 μmol/L, compared with the mother’s level of 370 μmol/L, a ratio of 0.32, but the milk:plasma ratio was 1.0 (5). One fully breastfed infant was sedated at birth with poor sucking and had no weight gain during 4 weeks of breastfeeding (4). Hyperexcitability lasting several weeks has been observed in infants exposed in utero to ethosuximide (4). This condition does not appear to be related to maternal use of the drug during breastfeeding because it also was noted in nonbreastfed infants. No other adverse effects in infants exposed to ethosuximide from milk have been reported. The American Academy of Pediatrics classifies ethosuximide as compatible with breastfeeding (21).
References
1.Product information. Ethosuximide. Pliva, 2009.
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3.The National Institute of Health. Anticonvulsants found to have teratogenic potential. JAMA 1981;241:36.
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16.The Lamotrigine Pregnancy Registry. Final Report. 1 September 1992 through 31 March 2010. GlaxcoSmithKline, July 2010.
17.Samren EB, van Duijn CM, Koch S, Hiilesmaa VK, Klepel H, Bardy AH, Beck Mannagetta G, Deichl AW, Gaily E, Granstrom ML, Meinardi H, Grobbee DE, Hofman A, Janz D, Lindhout D. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1992;38:981–90.
18.Koup JR, Rose JQ, Cohen ME. Ethosuximide pharmacokinetics in pregnant patient and her newborn. Epilepsia 1978;19:535.
19.Kaneko S, Sato T, Suzuki K. The levels of anticonvulsants in breast milk. Br J Clin Pharmacol 1979;7:624–6.
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21.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.